Traumatic brain injury (TBI) is one of the leading causes of disability in service personnel and veterans. The effects of TBI in surviving veterans can often be seen for decades after the initial injury. Oxidative stress and endoplasmic reticulum (ER) stress that starts within hours and continues for days are known promoters of neuronal death that lead to long-term neurological deficits after TBI. Importantly oxidative stress and ER stress potentiate each other and act synergistically. Hence, the goal of this proposal is to test if controlling oxidative stress and ER stress is beneficial after TBI. Oxidative stress is induced mainly by the reactive oxygen species (ROS). Hence, we will test a combo therapy that minimizes generation of ROS (by inhibiting NADPH oxidase NOX2) and concomitantly potentiates disposal of ROS (by inducing the antioxidant transcription factor Nrf2) decreases brain damage and promotes better motor and cognitive recovery following TBI. We will use a combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 inducer) in both males and females at different ages subjected to TBI. Furthermore, disruption of ER function after TBI leads to accumulation of unfolded proteins that start ER stress and also induce ROS generation. A major ER stress pathway is mediated by PERK and its downstream apoptotic genes. Hence, we will test if combining the antioxidant combo therapy with salubrinal (inhibitor of PERK pathway) provides a better efficacy to protect brain and promote functional recovery after TBI. We will also test the long-term consequences and the mechanisms of protection of the combo therapy in both males and females subjected to TBI. As a long-term complication of TBI is the development of Parkinson's disease (PD), we will test if the combo therapy during acute phase minimizes PD propensity during the chronic phase after TBI. We will test the hypothesis that an antioxidant combination therapy protects the brain and promotes long-term functional gains in both sexes at different ages after TBI. We further hypothesize that preventing oxidative stress and ER stress together is more efficacious to protect the brain and to promote neurological recovery after TBI. We also hypothesize that controlling oxidative stress decreases the propensity of Parkinson's disease (PD) pathology after TBI. ? Aim 1 will test the minimal efficacious dose, window of opportunity, effect of age and sex for the antioxidant combo (apocynin + TBHQ) therapy after TBI. ? Aim 2 will test if adding salubrinal increases the efficacy of antioxidant combo to protect brain and promotes better functional recovery after TBI. ? Aim 3 will test the long-term outcomes including motor function, cognitive function, neuropsychiatric function, gray and white matter damage and putative mechanisms of protection for the best combo therapy after TBI. This aim will further test if the combo therapy decreases the sensitivity of onset of PD-like pathology at a chronic stage after TBI. Overall, the present project will help us to find a drug combo that minimizes secondary brain damage and neurologic dysfunction after TBI by curtailing oxidative stress and ER stress after TBI. The long-term goal is to provide a therapy to help service personnel and veterans who suffer a TBI. Relevance of the proposed work to the VA patient care mission: Every year, thousands of service personnel will suffer TBI and many of those who survive struggle with long-term functional deficits. There are currently >300,000 veterans in USA who suffered a TBI. The negative impact of this devastating condition on veterans is enormous for the families as well as society in terms of financial loss and quality of life. Successful completion of the proposed studies to identify a drug combo that leads to better recovery of functions in surviving TBI sufferers will be enormously helpful to veterans.